Enteric and Diarrheal Disease

Richard Guerrant of the University of Virginia in the U.S. and co-investigators will develop and validate non-invasive metabolic biomarkers of gut health to identify children at risk of environmental enteropathy and developmental impairment, in order to assess interventions. They will use ongoing MAL-ED (malnutrition and enteric diseases) and NIH-supported clinical studies in malnourished and control children, and their own studies in novel murine models, along with a nuclear magnetic resonance approach to perform metabolic profiling of urine, plasma and feces samples.

Margaret Kosek of Johns Hopkins University in the U.S. and co-investigators will generate a new biomarker panel to assess disease activity in environmental enteropathy, which causes stunted growth and malnutrition. They will analyze markers related to immune system activation and growth factors in samples derived from the children enrolled in the MAL-ED (malnutrition and enteric diseases) study in Peru, and compare them with growth profiles and diarrheal disease burden as a proxy for disease activity.

William Faubion of the Mayo Clinic in the U.S. and colleagues will develop a non-invasive test of small intestinal permeability to improve the reliability of detection of environmental enteropathy, which causes childhood growth failure. The test involves quantification of sugar absorption in urine samples using mass spectrometry, and will be validated in at risk infants in the developing world. The aim is to provide a simple, safe and inexpensive test to identify all cases of this condition on a global scale, and drive the development of preventative interventions.

Mark Manary of Washington University in the U.S. and colleagues will develop a strategy for the non-invasive diagnosis of environmental enteropathy, which causes malnutrition and growth failure in young children in the developing world. They will devise a robust protocol to isolate human RNA of the small bowel from samples of stool, and will test a broad panel of candidate biomarkers for their ability to identify environmental enteropathy with high sensitivity using samples from at risk Malawian children.

Christopher Duggan of Children's Hospital Boston in the U.S. and his team will test whether known biomarkers of gut dysfunction can accurately predict impaired neurodevelopment and stunting, which reflects chronic malnutrition and is associated with increased morbidity and mortality in young children. The biomarkers will be validated in a well-characterized group of young Tanzanian children. The goal is to facilitate the identification of at risk children early in life, so that appropriate intervention strategies can be applied.

Pradip Maiti of Immunimed Inc. in Canada will provide passive immunotherapy using chicken-egg-derived polyclonal antibodies against key proteins of the intestinal parasite Cryptosporidium. This orally-administered immunotherapy will prevent the chronic diarrhea and potentially lethal infection caused by this parasite. Treating patients directly with antibodies against a pathogen is quicker than using traditional vaccination methods that induce individuals to make their own antibodies, which takes days to weeks and can also be difficult in malnourished children.

Sumiti Vinayak of the University of Georgia in the U.S. will develop a genetic tool to rapidly turn genes off using light in order to study the function of essential genes in the intestinal parasite Cryptosporidium and accelerate drug discovery. Cryptosporidium causes chronic diarrhea and can lead to death in young children. There is currently only one drug available and it is not effective in many patients.

Nigel Yarlett of Pace University in the U.S. will determine whether a virus that infects the intestinal parasite Cryptosporidium is a valuable target for developing drugs against the associated chronic diarrheal disease, which causes substantial morbidity and mortality in young children in low-resource settings. The double-stranded RNA Cryspoviruses are not harmful to the parasite, and instead likely enhance the parasite's ability to infect and harm humans.

Gregory Goldgof and Elizabeth Winzler of the University of California, San Diego in the U.S. will use a genetically modified drug-sensitive yeast strain to quickly and inexpensively identify the cellular target of compounds that can kill the parasite Cryptosporidium, which is a major cause of diarrhea-associated deaths of young children in developing countries. Currently, there is only one treatment available and it is of limited use in some of the more severe cases. The yeast strain has been modified to lack transporter proteins that remove toxic compounds from the yeast cells.

Phillip Tarr of Washington University in the U.S. is developing a method to evaluate gut permeability by measuring levels of ingested fluorescent molecules non-invasively through the skin. Gut permeability is increased in infants with environmental enteropathy, which is associated with impaired growth and development, and is prevalent in developing countries. Current tests are problematic due to the required collection and handling of body fluids from young children, and can produce varying results.